EP Vantage's InstablogEP Vantage is a forward-looking comment and analysis service tailored to the needs of pharma and finance professionals, focusing on the events that will define the future of companies, products and therapy areas. Written by experienced journalists, EP Vantage provides timely financial analysis of regulatory and patent decisions, marketing approvals, licensing deals, and M&A, giving fresh angles and insight to both current and future industry triggers. EP Vantage is powered by EvaluatePharma, the industry leader in consensus forecasts.EP Vantagehttp://seekingalpha.com/author/e/p/-/ep-vantage/instablog
Not For The Faint Of CAR-T - The CAR-T Landscape In Early 2015http://seekingalpha.com/instablog/374408-ep-vantage/3702436-not-for-the-faint-of-car-t-the-car-t-landscape-in-early-2015?source=feed
3702436This is an extract from a longer report

If you followed last year's explosion of enthusiasm in CAR therapies you might have assumed that this was a super-novel approach that had just burst onto the scientific stage. In fact work on the synthetic modification of a patient's T cells to make them target a specific disease has been ongoing for over 20 years.

But it is only relatively recently that two things happened: the CD19 antigen was pinpointed as an ideal target in haematological cancers thanks to its almost exclusive presence on B cells and

This marked the transformation of CARs from just another interesting scientific concept to one of today's most promising oncology therapies. Progress has accelerated since the 2013 American

Society of Hematology (ASH) meeting, and right now CAR therapy is already being hailed by some as a revolution that - in some patients - amounts to a cure.

While the science behind the current CAR constructs might be complex, the idea is actually relatively simple. In broad outline, the approach harnesses a patient's own immune system to direct it specifically against a disease.

A CAR is a synthetic receptor designed to target a specific tumour cell surface antigen, and the approach involves genetically modifying T cells (usually the patient's own) to make them express such a receptor on their surface.

The resulting CAR-T cells recognise the tumour antigen in question, and on binding with it the

CAR sends an intracellular signal to the T cell, prompting the destruction of the cancer cell.

UNTEMPERED ENTHUSIASM

A scientific advance of such magnitude has, naturally, been accompanied by untempered enthusiasm from investors desperate to jump into "the next big thing".

Look no further than the fund-raising record of Kite Pharma, Juno Therapeutics and Bellicum

Pharmaceuticals - three Nasdaq-listed US companies that offer pure-play exposure to cell therapy. All have seen huge demand for their offerings to the extent that every investor approach has yielded more cash than initially targeted.

A huge inflow of money into this space was triggered by the last edition of the ASH meeting, at which CAR therapies stole the show. Bellicum and Juno both floated on December 19, shortly after the meeting ended. Cellectis, a CAR-T company based in Paris and traded on the NYSE Alternext market, has announced plans for a secondary listing on Nasdaq.

Much potential lies in CAR therapy. However, with investors willing to value such early-stage technologies at such huge valuations, it is clear that important risks are being ignored.

The market appears to be steadfastly refusing to heed the lessons of the biotech boom and bust of 1999/2000.

Nevertheless, none of this means that CAR companies do not offer smart investors plenty of opportunities to benefit, and indeed in the early days of 2015 this space looks like being one of the top investment themes of the year.

THE SCIENCE

T-cell manipulation has a long history, having initially involved the expression of very basic CAR constructs in an effort to treat HIV. The first CARs had a very simple design, with a 1991 scientific paper describing a simple CD4 extracellular domain and an intracellular CD8ζ (zeta) intracellular signalling region.

Things moved on, and nowadays the favoured structure of a so-called second-generation CAR includes a complex scFv domain whose heavy and light chains mimic those of an antibody, plus an intracellular CD3 signalling section as well as a co-stimulatory domain (see below).

Third-generation CARs have two co-stimulatory domains to increase potency further, though work here is very early.

Second-generation CAR construct

When the CAR-engineered T cell engages the target cancer surface antigen it triggers further multiplication of the cells in the body, and activation of a cytotoxic (cell-killing) response. These

T cells have an "auto-regulatory" capability, in that they multiply in the presence of the target antigen, but their number falls as the target declines.

In its most advanced - autologous - version the actual therapy is a complex procedure, involving the collection of a patient's white blood cells via leukapheresis, and while these are outside the body certain T cells are isolated and transfected, usually using a viral vector, with the genetic material to make them express the desired CAR on their surface.

After this ex vivo modification the cells are expanded until their number reaches the desired "dose", whereupon they are infused back into the patient.

If you followed last year's explosion of enthusiasm in CAR therapies you might have assumed that this was a super-novel approach that had just burst onto the scientific stage. In fact work on the synthetic modification of a patient's T cells to make them target a specific disease has been ongoing for over 20 years.

But it is only relatively recently that two things happened: the CD19 antigen was pinpointed as an ideal target in haematological cancers thanks to its almost exclusive presence on B cells and

This marked the transformation of CARs from just another interesting scientific concept to one of today's most promising oncology therapies. Progress has accelerated since the 2013 American

Society of Hematology (ASH) meeting, and right now CAR therapy is already being hailed by some as a revolution that - in some patients - amounts to a cure.

While the science behind the current CAR constructs might be complex, the idea is actually relatively simple. In broad outline, the approach harnesses a patient's own immune system to direct it specifically against a disease.

A CAR is a synthetic receptor designed to target a specific tumour cell surface antigen, and the approach involves genetically modifying T cells (usually the patient's own) to make them express such a receptor on their surface.

The resulting CAR-T cells recognise the tumour antigen in question, and on binding with it the

CAR sends an intracellular signal to the T cell, prompting the destruction of the cancer cell.

UNTEMPERED ENTHUSIASM

A scientific advance of such magnitude has, naturally, been accompanied by untempered enthusiasm from investors desperate to jump into "the next big thing".

Look no further than the fund-raising record of Kite Pharma, Juno Therapeutics and Bellicum

Pharmaceuticals - three Nasdaq-listed US companies that offer pure-play exposure to cell therapy. All have seen huge demand for their offerings to the extent that every investor approach has yielded more cash than initially targeted.

A huge inflow of money into this space was triggered by the last edition of the ASH meeting, at which CAR therapies stole the show. Bellicum and Juno both floated on December 19, shortly after the meeting ended. Cellectis, a CAR-T company based in Paris and traded on the NYSE Alternext market, has announced plans for a secondary listing on Nasdaq.

Much potential lies in CAR therapy. However, with investors willing to value such early-stage technologies at such huge valuations, it is clear that important risks are being ignored.

The market appears to be steadfastly refusing to heed the lessons of the biotech boom and bust of 1999/2000.

Nevertheless, none of this means that CAR companies do not offer smart investors plenty of opportunities to benefit, and indeed in the early days of 2015 this space looks like being one of the top investment themes of the year.

THE SCIENCE

T-cell manipulation has a long history, having initially involved the expression of very basic CAR constructs in an effort to treat HIV. The first CARs had a very simple design, with a 1991 scientific paper describing a simple CD4 extracellular domain and an intracellular CD8ζ (zeta) intracellular signalling region.

Things moved on, and nowadays the favoured structure of a so-called second-generation CAR includes a complex scFv domain whose heavy and light chains mimic those of an antibody, plus an intracellular CD3 signalling section as well as a co-stimulatory domain (see below).

Third-generation CARs have two co-stimulatory domains to increase potency further, though work here is very early.

Second-generation CAR construct

When the CAR-engineered T cell engages the target cancer surface antigen it triggers further multiplication of the cells in the body, and activation of a cytotoxic (cell-killing) response. These

T cells have an "auto-regulatory" capability, in that they multiply in the presence of the target antigen, but their number falls as the target declines.

In its most advanced - autologous - version the actual therapy is a complex procedure, involving the collection of a patient's white blood cells via leukapheresis, and while these are outside the body certain T cells are isolated and transfected, usually using a viral vector, with the genetic material to make them express the desired CAR on their surface.

After this ex vivo modification the cells are expanded until their number reaches the desired "dose", whereupon they are infused back into the patient.

]]>
junokiteblcmnvsclrbbluecibsfPharmabiotechinvestinghealthcareHealthcare companies still desperate for a partner http://seekingalpha.com/instablog/374408-ep-vantage/10677-healthcare-companies-still-desperate-for-a-partner?source=feed
10677Six months on from EP Vantage’s review of companies in critical need of securing a partner for their late stage asset (Companies desperate for a partner, November 28, 2008), not only to commercialise the product but critically to provide much-needed cash, the same analysis reveals that the list has grown from 22 to 24 companies, with only Cougar Biotechnology truly successful in finding a partner following its recent takeover by Johnson & Johnson.

Almost two-thirds of the original list of 22 companies appear again (see table below), suggesting that the majority of partnering discussions have been slow to progress. Whilst the likes of Mannkind, NeurogesX and NicOx remain convinced that a major partnership is just around the corner, the going concern statements affecting others like Anesiva and Repros Therapeutics reflect the dangerous predicament a number of these companies are currently facing.

The following analysis presents essentially one-product companies, whose single-product NPV equals the total NPV, who have yet to sign a partner for their late stage asset in a major market.

Companies with a single product NPV = 100% of total NPV (ranked on years of cash)

Company

Product

Product Type

Phase

NPV ($m)

NPV as % of Market Cap

Latest Cash ($m)

Years of Cash

1

Advanced Life Sciences

Cethromycin (ABT-773)

Anti-bacterial

Filed

584 *

n/m

0.5

(0.9)

2

Anesiva

Adlea

Non-narcotic analgesic

Phase III

199

n/m

0.3

(0.8)

3

Repros Therapeutics

Proellex

Female sex hormone

Phase III

558

495%

12

(0.3)

4

MannKind

Afresa

Anti-diabetic

Filed

2,285

273%

30

(0.3)

5

Discovery Laboratories

Surfaxin

Other respiratory agent

Phase III

351

308%

19

(0.3)

6

Pharming

Rhucin

Other haematological

Phase III

332

393%

21

(0.1)

7

Arena Pharmaceuticals

Lorcaserin

Anti-obesity agent

Phase III

930

220%

70

(0.1)

8

NeurogesX

Qutenza

Non-narcotic analgesic

Filed

476

405%

19

0.0

9

Alexza Pharmaceuticals

AZ-004

Anti-psychotic

Phase III

455

548%

47

0.2

10

TiGenix

ChondroCelect

Other musculoskeletal agent

Filed

227

158%

29

0.3

11

Savient Pharmaceuticals

Krystexxa

Anti-gout preparation

Filed

664

88%

58

0.4

12

Somaxon Pharmaceuticals

Silenor

Sedatives & hypnotic

Filed

90

429%

4

0.4

13

BioMimetic Therapeutics

Augment OS1

Bone calcium regulator

Approved

991

506%

52

0.4

14

Poniard Pharmaceuticals

Picoplatin

Platinum compound

Phase III

289

172%

60

0.5

15

Protalix BioTherapeutics

prGCD

Other therapeutic product

Phase III

341

108%

35

0.5

16

OXiGENE

Zybrestat

Other cytostatic

Phase III

309

327%

27

0.6

17

Biodel

VIAject

Anti-diabetic

Phase III

841

669%

90

0.7

18

Acusphere

Imagify

Diagnostic imaging

Phase III

430

n/m

16

0.7

19

NicOx

HCT 3012

NSAID

Phase III

850

155%

110

0.9

20

Allos Therapeutics

PDX

Anti-metabolite

Filed

706

104%

131

1.0

21

Dyax

DX-88

Other haematological

Filed

595

462%

52

1.2

22

Cadence Pharmaceuticals

Acetavance (IV APAP)

Non-narcotic analgesic

Filed

807

180%

119

1.9

23

Clinical Data

Vilazodone

Anti-depressant

Phase III

2,360

810%

56

2.1

24

Dynavax Technologies

Heplisav

Vaccine

Phase III

95

160%

60

4.9

* NPV prior to negative FDA AdCom ruling on 3 June

Aside from Cougar’s takeover by J&J, the other companies no longer in the list for positive reasons are: Dendreon, reported positive phase III data for Provenge causing massive share price gains which enabled a decent equity issue (The Dendreon rollercoaster continues , April 29, 2009); MolMed, reported positive phase I data for Arenegyr which attracted new analyst valuations so de-risking their pipeline; Vanda Pharmaceuticals, who gained the surprise FDA approval of the decade for Fanapt (Vanda shares rocket after surprise Fanapt approval , May 7, 2009), the company is still in need of a partner but the product has yet to attract renewed analyst valuations.

Meanwhile, La Jolla Pharmaceutical also drops off the list, having almost produced a fairy-tale ending for its arduous development of lupus drug Riquent by signing a deal with BioMarin Pharmaceutical, only for the drug to fail in phase III trials (La Jolla drug failure leaves few options, February 12, 2009).

Current predicaments

Probably the most high profile name on the list is MannKind, the only company brave enough to be pushing on with an inhaled insulin product. At the recent American Diabetes Association meeting earlier this month, the company’s chief executive Alfred Mann was once again talking up prospects for a deal. Despite the company’s bullish stance real concerns over the approvability and commercial potential of the product exist. As such, the chance of securing a deal before the outcome of the January 15, 2010 PDUFA date is known, looks slim.

Advanced Life Sciences' chances of finding a partner for its antibiotic cethromycin were effectively dashed by a ruling by an FDA advisory committee earlier this month. The panel ruled in favour of the drug’s safety, but voted strongly against efficacy. A decision from the regulator due by July 31 is unlikely to be positive.

Although ALS has $2m cash at hand and has the option to draw down a further $12m over the next 15 months from a committed financing agreement, the outlook for the company appears fairly bleak. As such, if any partners are tempted, the asset is likely to be available a lot cheaper in the months ahead (Advanced Life Sciences reeling from FDA rejection June 3, 2009).

Anesiva meanwhile is in an even worse financial situation, its auditors having issued a going concern qualification in April, and its stock breaching Nasdaq listing rules. The group has pared back costs and plans to be operating largely as a virtual company by year end, in an attempt to keep hopes of finding a partner for Adlea, its long-acting, non-opioid analgesic drug candidate which is in development for the management of acute pain following orthopaedic surgery.

Savient Pharmaceuticals meanwhile has long been in search of a partner for its gout treatment Krystexxa, but has learnt the hard way about toying with investors’ expectations. A long promised deal failed to materialise in 2008, and the stock was hit hard (Savient's broken promises cause share woe, September 30, 2008). As a result, management are now refusing to comment on the situation, other than to say options are being explored, but following strong endorsement for the product at an FDA advisory committee earlier this week, ahead of an August 1 PDUFA, there is a good chance that Savient will not be on the same list in six months time.

Disclusre: No Positions

]]>
Tue, 30 Jun 2009 12:34:36 -0400Six months on from EP Vantage’s review of companies in critical need of securing a partner for their late stage asset (Companies desperate for a partner, November 28, 2008), not only to commercialise the product but critically to provide much-needed cash, the same analysis reveals that the list has grown from 22 to 24 companies, with only Cougar Biotechnology truly successful in finding a partner following its recent takeover by Johnson & Johnson.

Almost two-thirds of the original list of 22 companies appear again (see table below), suggesting that the majority of partnering discussions have been slow to progress. Whilst the likes of Mannkind, NeurogesX and NicOx remain convinced that a major partnership is just around the corner, the going concern statements affecting others like Anesiva and Repros Therapeutics reflect the dangerous predicament a number of these companies are currently facing.

The following analysis presents essentially one-product companies, whose single-product NPV equals the total NPV, who have yet to sign a partner for their late stage asset in a major market.

Companies with a single product NPV = 100% of total NPV (ranked on years of cash)

Company

Product

Product Type

Phase

NPV ($m)

NPV as % of Market Cap

Latest Cash ($m)

Years of Cash

1

Advanced Life Sciences

Cethromycin (ABT-773)

Anti-bacterial

Filed

584 *

n/m

0.5

(0.9)

2

Anesiva

Adlea

Non-narcotic analgesic

Phase III

199

n/m

0.3

(0.8)

3

Repros Therapeutics

Proellex

Female sex hormone

Phase III

558

495%

12

(0.3)

4

MannKind

Afresa

Anti-diabetic

Filed

2,285

273%

30

(0.3)

5

Discovery Laboratories

Surfaxin

Other respiratory agent

Phase III

351

308%

19

(0.3)

6

Pharming

Rhucin

Other haematological

Phase III

332

393%

21

(0.1)

7

Arena Pharmaceuticals

Lorcaserin

Anti-obesity agent

Phase III

930

220%

70

(0.1)

8

NeurogesX

Qutenza

Non-narcotic analgesic

Filed

476

405%

19

0.0

9

Alexza Pharmaceuticals

AZ-004

Anti-psychotic

Phase III

455

548%

47

0.2

10

TiGenix

ChondroCelect

Other musculoskeletal agent

Filed

227

158%

29

0.3

11

Savient Pharmaceuticals

Krystexxa

Anti-gout preparation

Filed

664

88%

58

0.4

12

Somaxon Pharmaceuticals

Silenor

Sedatives & hypnotic

Filed

90

429%

4

0.4

13

BioMimetic Therapeutics

Augment OS1

Bone calcium regulator

Approved

991

506%

52

0.4

14

Poniard Pharmaceuticals

Picoplatin

Platinum compound

Phase III

289

172%

60

0.5

15

Protalix BioTherapeutics

prGCD

Other therapeutic product

Phase III

341

108%

35

0.5

16

OXiGENE

Zybrestat

Other cytostatic

Phase III

309

327%

27

0.6

17

Biodel

VIAject

Anti-diabetic

Phase III

841

669%

90

0.7

18

Acusphere

Imagify

Diagnostic imaging

Phase III

430

n/m

16

0.7

19

NicOx

HCT 3012

NSAID

Phase III

850

155%

110

0.9

20

Allos Therapeutics

PDX

Anti-metabolite

Filed

706

104%

131

1.0

21

Dyax

DX-88

Other haematological

Filed

595

462%

52

1.2

22

Cadence Pharmaceuticals

Acetavance (IV APAP)

Non-narcotic analgesic

Filed

807

180%

119

1.9

23

Clinical Data

Vilazodone

Anti-depressant

Phase III

2,360

810%

56

2.1

24

Dynavax Technologies

Heplisav

Vaccine

Phase III

95

160%

60

4.9

* NPV prior to negative FDA AdCom ruling on 3 June

Aside from Cougar’s takeover by J&J, the other companies no longer in the list for positive reasons are: Dendreon, reported positive phase III data for Provenge causing massive share price gains which enabled a decent equity issue (The Dendreon rollercoaster continues , April 29, 2009); MolMed, reported positive phase I data for Arenegyr which attracted new analyst valuations so de-risking their pipeline; Vanda Pharmaceuticals, who gained the surprise FDA approval of the decade for Fanapt (Vanda shares rocket after surprise Fanapt approval , May 7, 2009), the company is still in need of a partner but the product has yet to attract renewed analyst valuations.

Meanwhile, La Jolla Pharmaceutical also drops off the list, having almost produced a fairy-tale ending for its arduous development of lupus drug Riquent by signing a deal with BioMarin Pharmaceutical, only for the drug to fail in phase III trials (La Jolla drug failure leaves few options, February 12, 2009).

Current predicaments

Probably the most high profile name on the list is MannKind, the only company brave enough to be pushing on with an inhaled insulin product. At the recent American Diabetes Association meeting earlier this month, the company’s chief executive Alfred Mann was once again talking up prospects for a deal. Despite the company’s bullish stance real concerns over the approvability and commercial potential of the product exist. As such, the chance of securing a deal before the outcome of the January 15, 2010 PDUFA date is known, looks slim.

Advanced Life Sciences' chances of finding a partner for its antibiotic cethromycin were effectively dashed by a ruling by an FDA advisory committee earlier this month. The panel ruled in favour of the drug’s safety, but voted strongly against efficacy. A decision from the regulator due by July 31 is unlikely to be positive.

Although ALS has $2m cash at hand and has the option to draw down a further $12m over the next 15 months from a committed financing agreement, the outlook for the company appears fairly bleak. As such, if any partners are tempted, the asset is likely to be available a lot cheaper in the months ahead (Advanced Life Sciences reeling from FDA rejection June 3, 2009).

Anesiva meanwhile is in an even worse financial situation, its auditors having issued a going concern qualification in April, and its stock breaching Nasdaq listing rules. The group has pared back costs and plans to be operating largely as a virtual company by year end, in an attempt to keep hopes of finding a partner for Adlea, its long-acting, non-opioid analgesic drug candidate which is in development for the management of acute pain following orthopaedic surgery.

Savient Pharmaceuticals meanwhile has long been in search of a partner for its gout treatment Krystexxa, but has learnt the hard way about toying with investors’ expectations. A long promised deal failed to materialise in 2008, and the stock was hit hard (Savient's broken promises cause share woe, September 30, 2008). As a result, management are now refusing to comment on the situation, other than to say options are being explored, but following strong endorsement for the product at an FDA advisory committee earlier this week, ahead of an August 1 PDUFA, there is a good chance that Savient will not be on the same list in six months time.